(a) Field of The Invention
The present invention relates to chemical compounds that activate the insulin receptor kinase, and to methods for treating humans with hyperglycemia, especially for the treatment of Type II diabetes.
(b) Description of Related Art
Peptide and protein hormones, such as insulin, interact with receptors with high specificity. The insulin receptor is present on virtually all cells and at high concentrations on the cells for the liver, skeletal muscles, and adipose tissue. Stimulation of the insulin receptor with insulin is an essential element in carbohydrate metabolism and storage.
Diabetics either lack sufficient endogenous secretion of the insulin hormone (Type I diabetes) or have an insulin receptor-mediated signaling pathway that is resistant to endogenous or exogenous insulin (Type II diabetes, or non-insulin-dependent diabetes mellitus (NIDDM)). Type II diabetes is the most common form of diabetes, affecting about 5% of individuals in the industrialized nations. In Type II diabetics, major insulin-responsive tissues such as liver, skeletal muscle, and fat exhibit insulin resistance [Haring and Mehnert, Diabetologia 36:176-182 (1993); Haring et al., Diabetologia, 37 Suppl. 2:S149-54 (1994)]. The resistance to insulin in Type II diabetes is complex and likely multi-factorial but appears to be caused by an impaired signal from the insulin receptor to the glucose transport system and to glycogen synthase. Impairment of the insulin receptor kinase has been implicated in the pathogenesis of this signaling defect. Insulin resistance is also found in many non-diabetic individuals and may be an underlying etiologic factor in the development of the disease [Reaven, Diabetes, 37:1595-1607 (1988)].
Considerable information is known concerning the insulin receptor itself. The receptor consists of four separate subunits consisting of two identical xcex1 and two identical xcex2 chains. The xcex2 subunits contain tyrosine kinase activity and the ATP binding sites. The insulin receptor is activated by autophosphorylation of key tyrosine residues in its cytoplasmic tyrosine kinase domain. This autophosphorylation is required for subsequent activity of the insulin receptor. The autophosphorylation stabilizes the activated receptor kinase, resulting in a phosphorylation cascade involving intracellular signaling proteins.
At present, there are limited pharmacological approaches to treatment of Type II diabetes. Insulin is currently used as a treatment but is disadvantageous, because insulin must be injected. Although several peptide analogs of insulin have been described, none with a molecular weight below 5000 Dalton retains activity. Some peptides which interact with sites on the xcex2-subunit of the insulin receptor have shown enhancement of the activity of insulin on its receptor [Kole et al., J. Biol. Chem. 271:31619-31626 (1996); Kasuya et al., Biochem. Biophys. Res. Commun., 200:777-783 (1994)]. Kohanski and others have reported on a variety of polycationic species that generate a basal effect but do little to enhance insulin action [Kohanski, J. Biol. Chem. 264:20984-20991 (1989); Xu et al., Biochemistry 30:11811-11819 (1991)]. These peptides apparently act on the cytoplasmic kinase domain of the insulin receptor.
In addition, certain non-peptide components have been found to enhance the effects of insulin, but none appear to act directly on the insulin receptor kinase. For example, thiazolidinediones, such as pioglitazone, enhance adipocyte differentiation [Kletzien et al., Mol. Pharmacol. 41:393 (1992). These thiazolidinediones represent a class of potential anti-diabetic compounds that enhance the response of target tissues to insulin [Kobayashi, Diabetes, 41:476 (1992)]. The thiazolidinediones switch on peroxisome proliferator-activated receptor xcex3 (PPARxcex3), the nuclear transcription factor involved in adipocyte differentiation [Kliewer et al., J. Biol. Chem., 270:12953 (1995)], and do not have a direct effect on the insulin receptor kinase. Other anti-diabetic agents currently in use include both insulin secretagogues (such as the sulfonylureas) and biguanides (such as methformin) that inhibit hepatic glucose output.
Stilbenes and derivatives are prevalent throughout the chemical literature, with a large number of functionalized stilbenes described. Tri- and tetra- aryl stilbenes are known but have relatively few examples. The substituted stilbenes have biological activity and are reported as treatments to inflammatory and proliferative skin diseases [Nusbaumer, PCT International Publication No. WO 96/28430], as a method for inhibiting apoptosis [Babior et al., PCT International Publication No. WO 9634604], and as anti-virals [Haugwitz et al., PCT International Publication No. WO 9625399]. Tetra-substituted stilbenes, such as tamoxifen, are used in treating breast cancer [Furr et al., Pharmacol. Ther. 25:127-205 (1984)]. There is extensive literature describing the use of the stilbenes in the preparation of interesting polymers.
The disclosures of these and other documents referred to elsewhere in this application are incorporated herein by reference.
In a first aspect, the invention is compounds of formula I: 
where
R1, R3, and R4 are, independently, hydrogen, lower alkyl, substituted lower alkyl, halo, hydroxyl, optionally substituted lower alkyloxy, xe2x80x94NR11R12, or xe2x80x94C(O)NR11R12, where R11 and R12 are, independently, hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, aryl(lower)alkyl, substituted aryl(lower)alkyl, heteroaryl(lower)alkyl, substituted heteroaryl(lower)alkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl, or xe2x80x94C(O)OR13 where R13 is hydrogen or lower alkyl;
R2 is hydrogen, lower alkyl, substituted lower alkyl, halo, hydroxyl, lower alkoxy, substituted lower alkyloxy, carboxyl, xe2x80x94NR11R12, xe2x80x94NR11C(O)R12, or xe2x80x94C(O)NR11R12, where R11 and R12 have the above meanings, or
R2 and R3, together with the carbon atoms to which they are attached, form a heterocyclic ring;
R5 is hydrogen, lower alkyl, substituted lower alkyl, or aryl;
R6 and R7 are, independently, hydrogen, lower alkyl or xe2x80x94C(O)OR13, where R13 has the above meaning;
R8 and R9 are, independently, hydrogen, lower alkyl, substituted lower alkyl, halo, hydroxyl, lower alkoxy, carboxyl, xe2x80x94NR11R12, or xe2x80x94C(O)N R11R12, where R11 and R12 have the above meanings,
R10 is hydrogen, lower alkyl, substituted lower alkyl, halo, hydroxy, lower alkoxy, xe2x80x94C(O)OR13 where R13 is hydrogen or lower alkyl, xe2x80x94SO3H, or xe2x80x94C(O)NR11R12, where R11 and R12 have the above meanings;
and the pharmaceutically acceptable salts thereof; as single stereoisomers or mixtures of stereoisomers.
These compounds are useful for stimulating and/or enhancing the uptake of glucose into cells in a mammal or for treating a mammalian disease state selected from the group consisting of hyperglycemia, type I diabetes, and type II diabetes.
In a second embodiment, this invention is pharmaceutical compositions comprising (a) at least one pharmaceutically acceptable carrier and (b) a compound of the first aspect of the invention as the active ingredient.
These compositions are useful for stimulating and/or enhancing the uptake of glucose into cells in a mammal or for treating a mammalian disease state selected from the group consisting of hyperglycemia, type I diabetes, and type II diabetes.
In a third embodiment, this invention is methods of treatment of hyperglycemia, type I diabetes, or type 1I diabetes in a mammal, such as a human, by administering a therapeutically effective amount of a compound of the first aspect of the invention, or a composition of the second aspect of the invention.
In a fourth embodiment, this invention is a method of stimulating the kinase activity of the insulin receptor or activating the insulin receptor, comprising contacting the insulin receptor or the kinase portion thereof with a compound of the first aspect of the invention in an amount sufficient to stimulate the kinase activity of the insulin receptor or activate the insulin receptor.
In a fifth embodiment, this invention provides a method for stimulating the uptake of glucose into cells which display the insulin receptor, comprising contacting the cells, in the presence of insulin, with a compound of the first aspect of the invention in an amount sufficient to stimulate the uptake of glucose into the cells. The uptake of glucose into cells in a mammal may be effected by administering the compound, or a composition containing it, to the mammal.
In a sixth embodiment, this invention provides processes for the preparation of compounds of formula I or pharmaceutically acceptable salts thereof.
Certain compounds of formula I are useful as intermediates to prepare other compounds of formula I with higher activity.
xe2x80x9cAlkylxe2x80x9d means a linear C1-20 monovalent hydrocarbyl group or a branched or cyclic C3-20 monovalent hydrocarbyl group.
xe2x80x9cLower alkylxe2x80x9d, as in xe2x80x9clower alkylxe2x80x9d, xe2x80x9chalo-lower alkylxe2x80x9d, xe2x80x9caryl(lower)alkylxe2x80x9d, or xe2x80x9cheteroaryl(lower)alkylxe2x80x9d, means a C1-10 alkyl. The term xe2x80x9clower alkylxe2x80x9d includes such groups as methyl, ethyl, isopropyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, n-decyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclohexyl, or cyclohexylmethyl. C1-6 lower alkyls are preferred. xe2x80x9cLower alkyloxyxe2x80x9d is a group of the formula xe2x80x94Oxe2x80x94Ra where Ra is a xe2x80x9clower alkylxe2x80x9d as defined above.
xe2x80x9cSubstituted alkylxe2x80x9d or xe2x80x9csubstituted lower alkylxe2x80x9d indicates that the alkyl group or the lower alkyl group is typically mono-, di-, or tri-substituted with a moiety such as aryl, Rxe2x80x2-substituted aryl, heteroaryl, nitro, cyano, halo, xe2x80x94OR, xe2x80x94SR, xe2x80x94C(O)R, xe2x80x94OC(O)R, xe2x80x94C(O)OR, xe2x80x94NR2, xe2x80x94OSO2R, xe2x80x94SO2OR, xe2x80x94SO2NR2, xe2x80x94NRSO2R, xe2x80x94C(O)NR2, or xe2x80x94NRC(O)R, where each R is, independently, hydrogen, lower alkyl, Rxe2x80x2-substituted lower alkyl, aryl, Rxe2x80x2-substituted aryl, heteroaryl, heteroaryl(lower)alkyl, Rxe2x80x2-substituted aryl(lower) alkyl, or aryl(lower)alkyl and each Rxe2x80x2 is, independently, hydroxy, halo, lower alkyloxy, cyano, thio, nitro, lower alkyl, halo-lower alkyl, amino, or xe2x80x94C(O)ORb where Rb is hydrogen or alkyl. Substituted alkyls or substituted lower alkyls which are substituted with one to three of the substituents selected from the group consisting of cyano, halo, lower alkyloxy, thio, nitro, amino, or hydroxy are particularly preferred.
xe2x80x9cSubstituted alkyloxyxe2x80x9d or xe2x80x9csubstituted lower alkyloxyxe2x80x9d is a group of the formula xe2x80x94Oxe2x80x94Rc where Rc is xe2x80x9csubstituted alkylxe2x80x9d or xe2x80x9csubstituted lower alkylxe2x80x9d as defined above.
xe2x80x9cHalo-lower alkylxe2x80x9d means a lower alkyl substituted with one to three halo groups, and is further exemplified by such groups as xe2x80x94CF3, xe2x80x94CH2CF3 and xe2x80x94CH2CCl3.
xe2x80x9cArylxe2x80x9d, as in xe2x80x9carylxe2x80x9d, xe2x80x9caryloxyxe2x80x9d, and xe2x80x9caryl(lower)alkylxe2x80x9d, means a group derived from an aromatic hydrocarbon containing 6 to 20 ring carbon atoms, having a single ring (e.g., phenyl), two or more condensed rings, preferably 2 to 3 condensed rings (e.g., naphthyl), or two or more aromatic rings, preferably 2 or 3 aromatic rings, which are linked by a single bond (e.g., biphenyl). The aryl is preferably C6-C16 and even more preferably, C6-C14.
A xe2x80x9csubstituted arylxe2x80x9d is an aryl group which is typically mono-, di-, or tri-substituted, independently, with a moiety such as lower alkyl, Rd-substituted lower alkyl, nitro, cyano, halo, xe2x80x94ORe, xe2x80x94SRe, xe2x80x94C(O)Re, xe2x80x94C(O)ORe, xe2x80x94OC(O)Re, xe2x80x94NRe2, xe2x80x94OSO2Re, xe2x80x94SO2ORe, xe2x80x94SO2NRe2, xe2x80x94NRSO2Re, xe2x80x94C(O)NRe2, or xe2x80x94NRC(O)Re, where each Rd is, independently, hydroxy, halo, lower alkyloxy, cyano, thio, nitro, lower alkyl, halo-lower alkyl, or amino, and each Reis, independently, hydrogen, lower alkyl, Rd-substituted lower alkyl, aryl, Rd-substituted aryl, heteroaryl, heteroaryl(lower)alkyl, Rd-substituted aryl(lower) alkyl, or aryl(lower)alkyl. Especially preferred substituents on a substituted aryl are lower alkyl, halo-lower alkyl, halo, cyano, thio, nitro, amino, lower alkyloxy, hydroxy, xe2x80x94SO2ORf, xe2x80x94SO2NRf2, xe2x80x94C(O)ORf, and xe2x80x94C(O)NRf2, where Rf is a hydrogen or lower alkyl.
xe2x80x9cHeteroarylxe2x80x9d, as in xe2x80x9cheteroarylxe2x80x9d and xe2x80x9chetero(lower)alkylxe2x80x9d, means a group derived from an aromatic hydrocarbon containing 5 to 14 ring atoms, 1 to 5 of which are hetero atoms chosen, independently, from N, O, or S, and includes monocyclic, condensed heterocyclic, and condensed carbocyclic and heterocyclic aromatic rings (e.g. thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxazolyl, indolyl, isobenzofuranyl, purinyl, isoquinolyl, pteridinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, quinolyl, etc.).
A xe2x80x9csubstituted heteroarylxe2x80x9d may have from one to three substituents such as lower alkyl, Rd-substituted lower alkyl, nitro, cyano, halo, xe2x80x94ORg, xe2x80x94SRg, xe2x80x94C(O)Rg, xe2x80x94C(O)ORg, xe2x80x94OC(O)Rg, xe2x80x94NRg2, xe2x80x94OSO2Rg, xe2x80x94SO2ORg, xe2x80x94SO2NRg2, xe2x80x94NRSO2Rg, xe2x80x94C(O)NRg2, or xe2x80x94NRC(O)Rg, where each Rg is, independently, hydrogen, lower alkyl, Rd-substituted lower alkyl, aryl, Rd-substituted aryl, heteroaryl, heteroaryl(lower)alkyl, Rd-substituted aryl(lower) alkyl, or aryl(lower)alkyl and each Rd is as defined above. In addition, any two adjacent substituents on the heteroaryl may optionally together form a lower alkylenedioxy. Particularly preferred substituents on the heteroaryl include hydroxy, halo, lower alkyloxy, cyano, thio, nitro, lower alkyl, halo-lower alkyl, or ammo.
xe2x80x9cHeterocyclylxe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d means a saturated cyclic (mono- or bicyclic) group containing 5 to 14 ring atoms and having at least one ring atom other than carbon. Preferably, 1 to 5 of the hetero atoms are chosen, independently, from N, O, or S. Monocyclic heterocyclyls are, for example, tetrahydrofuranyl, tetrapyranyl, piperidinyl, etc.
A xe2x80x9csubstituted heterocyclylxe2x80x9d may have from one to three substituents such as lower alkyl, Rd-substituted lower alkyl, nitro, cyano, halo, xe2x80x94ORg, xe2x80x94SRg, xe2x80x94C(O)Rg, xe2x80x94C(O)ORg, xe2x80x94OC(O)Rg, xe2x80x94NRg2, xe2x80x94OSO2Rg, xe2x80x94SO2ORg, xe2x80x94SO2NRg2, xe2x80x94NRSO2Rg, xe2x80x94C(O)NRg2, or xe2x80x94NRC(O)Rg, where each Rgis, independently, hydrogen, lower alkyl, Rd-substituted lower alkyl, aryl, Rd-substituted aryl, heteroaryl, heteroaryl(lower)alkyl, Rd-substituted aryl(lower) alkyl, or aryl(lower)alkyl and each Rd is as defined above. Preferred substituents on a substituted heterocyclyl include lower alkyl, halo-lower alkyl, cyano, thio, amino, lower alkyloxy, or hydroxy.
xe2x80x9cAryl(lower)alkylxe2x80x9d means a lower alkyl group which is substituted with an aryl group, as previously defined. A xe2x80x9csubstituted aryl(lower)alkylxe2x80x9d means an aryl(lower)alkyl group having one to three substituents on the aryl portion or the alkyl portion of the group, or both.
xe2x80x9cHeteroaryl(lower)alkylxe2x80x9d means a lower alkyl group which is substituted with a heteroaryl group, as previously defined. A xe2x80x9csubstituted heteroaryl(lower)alkylxe2x80x9d means a heteroaryl(lower)-alkyl group having one to three substituents on the heteroaryl portion or the alkyl portion of the group, or both.
xe2x80x9cHaloxe2x80x9d means bromo, iodo, fluoro, or chloro.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d may be any salt derived from an inorganic or organic acid or an inorganic or organic base. The term xe2x80x9cpharmaceutically acceptable anionxe2x80x9d refers to the anion of such acid addition salts. The term xe2x80x9cpharmaceutically acceptable cationxe2x80x9d refers to a cation formed by addition of base.
xe2x80x9cInner saltsxe2x80x9d or xe2x80x9czwitterionsxe2x80x9d can be formed by transferring a proton from a carboxyl group onto the lone pair of electrons of the nitrogen atom in an amino group if both such groups are present in the compound.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount which, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease in a mammal includes:
(1) preventing the disease from occurring in a mammal which may be predisposed to the disease but does not yet experience or display symptoms of the disease;
(2) inhibiting the disease, i.e., arresting its development, or
(3) relieving the disease, i.e., causing regression of the disease.
xe2x80x9cDiseasexe2x80x9d here includes hyperglycemia and diabetes (both Type I and Type A).
The xe2x80x9ckinase portion thereofxe2x80x9d, with respect to the insulin receptor, means the cytoplasmic tyrosine kinase domain of the insulin receptor.
xe2x80x9cStereoisomersxe2x80x9d means compounds that have the same sequence of covalent bonds and differ in the relative disposition of their atoms in space.
In a first aspect, the invention is compounds of formula I: 
where
R1, R3, and R4 are, independently, hydrogen, lower alkyl, substituted lower alkyl, halo, hydroxyl, optionally substituted lower alkyloxy, xe2x80x94NR11R12, or xe2x80x94C(O)NR11R12, where R11 and R12 are, independently, hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, aryl(lower)alkyl, substituted aryl(lower)alkyl, heteroaryl(lower)alkyl, substituted heteroaryl(lower)alkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl, or xe2x80x94C(O)OR13 where R13 is hydrogen or lower alkyl;
R2 is hydrogen, lower alkyl, substituted lower alkyl, halo, hydroxyl, lower alkoxy, substituted lower alkyloxy, carboxyl, xe2x80x94NR11R12, xe2x80x94NR11C(O)R12, or xe2x80x94C(O)NR11R12, where R11 and R12 have the above meanings, or
R2 and R3, together with the carbon atoms to which they are attached, form a heterocyclic ring;
R5 is hydrogen, lower alkyl, substituted lower alkyl, or aryl;
R6 and R7 are, independently, hydrogen, lower alkyl or xe2x80x94C(O)OR13, where R13 has the above meaning;
R8 and R9 are, independently, hydrogen, lower alkyl, substituted lower alkyl, halo, hydroxyl, lower alkoxy, carboxyl, xe2x80x94NR11R12, or xe2x80x94C(O)N R11R12, where R11 and R12 have the above meanings,
R10 is hydrogen, lower alkyl, substituted lower alkyl, halo, hydroxy, lower alkoxy, xe2x80x94C(O)OR13 where R13 is hydrogen or lower alkyl, xe2x80x94SO3H, or xe2x80x94C(O)NR11R12, where R11 and R12 have the above meanings;
and the pharmaceutically acceptable salts thereof; as single stereoisomers or mixtures of stereoisomers.
In a first preferred embodiment, R6 is xe2x80x94C(O)OR13. More preferably, R1R4 are independently hydrogen, hydroxyl, lower alkoxy, or substituted lower alkoxy such as OCH2CO2R13or OCH2PhCO2R13 in which Ph is phenylene. Certain compounds of this preferred embodiment are useful as intermediates to prepare other compounds of formula I with higher activity.
In a second preferred embodiment, R2 is NR11R12 where R11 and R12 are independently hydrogen, lower alkyl, substituted lower alkyl, aryl, or substituted aryl. Certain compounds of this preferred embodiment are useful as intermediates to prepare other compounds of formula I with higher activity.
In a third preferred embodiment, R2 is N(R11)C(O)R12 where R11 and R112 are independently hydrogen, lower alkyl, substituted lower alkyl, aryl, or substituted aryl. Certain compounds of this preferred embodiment are useful as intermediates to prepare other compounds of formula I with higher activity. Within this third preferred embodiment, more preferably, R11 is hydrogen or lower alkyl and R12 is 4-(R13-oxycarbonyl)phenyl. Certain compounds of these preferred embodiments are useful as intermediates to prepare other compounds of formula I with higher activity.
In a fourth preferred embodiment of the invention, R1-R3 and R6-R9 are independently hydrogen or lower alkyl, R4 is xe2x80x94C(O)OR13, and R10 is lower alkyl or substituted lower alkyl. Certain compounds of this preferred embodiment are useful as intermediates to prepare other compounds of formula I with higher activity.
In a fifth preferred embodiment of the invention, R1-R6 and R8-R10 are independently hydrogen or lower alkyl, and R7 is xe2x80x94C(O)OR13. Certain compounds of this preferred embodiment are useful as intermediates to prepare other compounds of formula I with higher activity.
In a sixth preferred embodiment of the invention, R1 and R4-R9 are hydrogen or lower alkyl, R2 and R3, together with the carbon atoms to which they are attached, form a heterocyclic ring, and R10 is hydroxy or alkoxy. Certain compounds of this preferred embodiment are useful as intermediates to prepare other compounds of formula I with higher activity.
In a seventh preferred embodiment, R1, R3-R5, and R7-R9 are hydrogen, R2 is xe2x80x94NHCH3, and R6 is xe2x80x94CO2H.
In a particularly preferred embodiment of the present invention, R1, R3, R4, and R7-R9 are hydrogen, R2 is xe2x80x94N(CH3)C(O)(4-carboxyphenyl), R5 is methyl, R6 is xe2x80x94CO2H, and R10 is xe2x80x94CH2CO2H.
Compounds of the present invention include, but are not limited to, the following compounds:
5-((1E)-2-phenylvinyl)-2-({4-[(4-carboxyphenyl)-N-methylcarbonylamino]phenyl}-N-methyl carbonylamino)benzoic acid;
4-((1E)-2-{4-[(4-{[4-(methoxycarbonyl)phenyl]N-methylcarbonylamino}phenyl)-carbonyl amino]phenyl}vinyl)benzoic acid;
5-[(1E)-2-(4-carboxyphenyl)vinyl]-2-{[4-(methylamino)phenyl]carbonylamino}benzoic acid;
2-[N-(4-{(1E)-2-[4-(carboxymethyl)phenyl]vinyl}phenyl)carbamoyl]benzoic acid;
5-((1E)-2-phenylvinyl)-2-(N-methylphenylcarbonylamino)benzoic acid;
5-((1E)-2-phenylvinyl)-2-[(3,4,5-trimethoxyphenyl)carbonylamino]benzoic acid;
methyl 5-((1E)-2-phenylvinyl)-2-(phenylcarbonylamino)benzoate;
5-[(1E)-2-(4-methoxyphenyl)vinyl]-2-(N-methylphenylcarbonylamino)benzoic acid;
methyl 4-{N-[4-(N-{4-[(1E)-2-(4-methoxyphenyl)vinyl]-2-(methoxycarbonyl)phenyl}carbamoyl)phenyl]-N-methylcarbamoyl}benzoate;
5-[(1E)-2-(4-methoxyphenyl)vinyl]-2-[(4-{[4-(methoxycarbonyl)phenyl]N-methylcarbonyl amino}phenyl)carbonylamino]benzoic acid;
5-[(1E)-2-(4-methoxyphenyl)vinyl]-2-({4-[(4-carboxyphenyl)-N-methylcarbonylamino]phenyl}carbonylamino)benzoic acid;
methyl 4-{N-[4-(N-{4-[(1E)-2-(2-fluorophenyl)vinyl]-2-(methoxycarbonyl)phenyl}carbonyl)-phenyl]-N-methylcarbamoyl}benzoate;
5-[(1E)-2-(2-fluorophenyl)vinyl]-2-({4-[(4-carboxyphenyl)-N-methylcarbonyl-amino]phenyl}carbonylamino)benzoic acid;
methyl 4-{N-[4-(N-{4-[(1E)-2-(4-fluorophenyl)vinyl]-2-(methoxycarbonyl)phenyl}phenyl]-N-methylcarbamoyl}benzoate;
5-[(1E)-2-(4-fluorophenyl)vinyl]-2-({4-[(4-carboxyphenyl)-N-methylcarbonylamino]phenyl}carbonylamino)benzoic acid;
4-((1E)-2-{3-(methoxycarbonyl)-4-[(4-{[4-(methoxycarbonyl)phenyl]-N-methylcarbonyl amino}phenyl)carbonylamino]phenyl}vinyl)benzenesulfonic acid;
methyl 4-{N-[4-(N-{4-[(1E)-2-(3-fluorophenyl)vinyl]-2-(methoxycarbonyl)phenyl}carbonyl)phenyl]-N-methylcarbamoyl}benzoate;
2-((1E)-2-phenylvinyl)-5-(phenycarbonylamino)benzoic acid;
2-((1E)-2-phenylvinyl)-5-[(4-{[4-(methoxycarbonyl)phenyl]-N-methylcarbonylamino}phenyl) carbonylamino]benzoic acid;
methyl 4-[N-(4-{N-[4-((1E)-2-phenylvinyl)-2-(methoxycarbonyl)phenyl]-carbamoyl}phenyl)-N-methylcarbamoyl]benzoate;
5-((1E)-2-phenylvinyl)-2-[(3,5-dihydroxyphenyl)carbonylamino]benzoic acid;
5-((1E)-2-phenylvinyl)-2-[(3-methoxyphenyl)carbonylamino]benzoic acid;
5-((1E)-2-phenylvinyl)-2-({4-[(4 -carboxyphenyl)-N-methylcarbonylamino]phenyl}carbonyl amino)benzoic acid;
methyl 4-(N-{4-[N-(4-{(1E)-2-[4-(methoxycarbonyl)phenyl]vinyl}phenyl)-carbamoyl]phenyl}-N-methylcarbamoyl)benzoate;
2-[3-((1E)-2-{4-[(4-{[4-(methoxycarbonyl)phenyl]-N-methylcarbonylamino}phenyl)-N-methyl carbonylamino]phenyl}vinyl)phenyl]acetic acid;
2-[3-((1E)-2-{4-[(4-{[4-(methoxycarbonyl)phenyl]-N-methylcarbonylamino}phenyl)carbonyl amino]phenyl}vinyl)phenyl]acetic acid;
4-((1E)-2-{4-[(4-{[4-(methoxycarbonyl)phenyl]-N-methylcarbonylamino}phenyl)-N-methyl carbonylamino]phenyl}vinyl)benzoic acid;
methyl 4-(N-{4-[N-(4-{(1E)-2-[4-(methoxycarbonyl)phenyl]vinyl}phenyl)-N-methyl carbamoyl]phenyl}-N-methylcarbamoyl)benzoate;
5-((1E)-2-{4-[(4-{[4-(methoxycarbonyl)phenyl]-N-methylcarbonylamino}phenyl)-N-methyl carbonylamino]phenyl}vinyl)-2-(tert-butoxy)benzoic acid;
5-{(1E)-2-[4-({4-[(4-carboxyphenyl)-N-methylcarbonylamino]phenyl}-N-methylcarbonyl amino)phenyl]vinyl}-2-(tert-butoxy)benzoic acid;
5-{(1E)-2-[4-({4-[(4-carboxyphenyl)-N-methylcarbonylamino]phenyl}N-methylcarbonyl amino)phenyl]vinyl}-2-hydroxybenzoic acid;
methyl 5-((1E)-2-phenylvinyl)-2-[(3,4-dimethoxyphenyl)carbonylammo]benzoate;
5-((1E)-2-phenylvinyl)-2-[(3,4-dimethoxyphenyl)carbonylamino]benzoic acid;
5-((1E)-2-phenylvinyl)-2-[(3,5-dimethoxyphenyl)carbonylamino]benzoic acid;
2-{5-((1E)-2-phenylvinyl)-2-[(3-methoxyphenyl)carbonylamino]phenyl}acetic acid;
N-{4-[(1E)-2-(4-methoxyphenyl)vinyl]phenyl}-2H-benzo[d]1,3-dioxolen-5-ylcarboxamide;
5-[(1E)-2-(4-methoxyphenyl)vinyl]-2-(N-[(4-carboxyphenyl)methyl]{4-[(4-carboxyphenyl)-N-methylcarbonylamino]phenyl}carbonylamino)benzoic acid;
2-((1E)-2-phenylvinyl)-5-({4-[(4-carboxyphenyl)-N-methylcarbonylamino]phenyl} carbonyl amino)benzoic acid;
5-((1E)-2-phenylvinyl)-2-{[3,5-bis(carboxymethoxy)phenyl]carbonylamino}benzoic acid;
5-((1E)-2-phenylvinyl)-2-({3,5-bis[(4-carboxyphenyl)methoxy]phenyl}carbonylamino)benzoic acid; and
5-((1E)-2-phenylvinyl)-2-({3,5-bis[(3-carboxyphenyl)methoxy]phenyl}carbonylamino)benzoic acid,
and pharmaceutically acceptable salts thereof.
A process for preparing the compounds is described below, and descriptions of these compounds are outlined in Examples 1-3, likewise below.
Certain compounds of the invention may contain one or more chiral centers. In such cases, all stereoisomers also fall within the scope of this invention. The invention compounds include the individually isolated stereoisomers as well as mixtures of such stereoisomers.
The compounds of the invention further comprise pharmaceutically acceptable salts of the compounds disclosed herein. These pharmaceutically acceptable salts are suitable for use in all methods and pharmaceutical compositions of the present invention.
Pharmaceutically acceptable salts include salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Typically, the parent compound is treated with an excess of an alkaline reagent, such as hydroxide, carbonate, or alkoxide, containing an appropriate cation. Cations such as Na+, K+, Ca2+, and NH4+are examples of cations present in pharmaceutically acceptable salts. The Na+ salts are especially useful. Acceptable inorganic bases, therefore, include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium hydroxide, and sodium carbonate. Salts may also be prepared using organic bases, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and tromethamine.
If the compound of the invention contains a basic group, an acid addition salt may be prepared. Acid addition salts of the compounds are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate salts), nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, salicylic acid, p-toluenesulfonic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, lactic acid, o-(4-hydroxy-benzoyl)benzoic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, gluconic acid, 4,4xe2x80x2-methylenebis(3-hydroxy-2-naphthoic)acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, laurylsulfuric acid, glucuronic acid, glutamic acid, 3-hydroxy-2-naphthoic acid, stearic acid, muconic acid and the like.
Certain of the compounds of the invention form inner salts or zwitterions.
Pharmaceutical compositions of all of the compounds in the present invention are contemplated. These pharmaceutical compositions comprise (i) a compound of the invention as an active ingredient and (ii) at least one pharmaceutically acceptable carrier.
Pharmaceutical compositions of the compounds of this invention, or derivatives thereof, may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulations are especially suitable parenteral administration, but may also be used for oral administration. It may be desirable to add excipients such as polyvinylpyrrolidinone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride, or sodium citrate. Alternatively, these compounds may be encapsulated, tableted, or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar, or gelatin. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
The amount of a compound of formula I in the composition may vary widely, depending on the type of composition, size of unit dosage, kind of excipient(s), and other factors known to those skilled in the art of pharmaceutical sciences. In general, the final composition will comprise from 1% w/w to 99% w/w, more preferably, 10% w/w to 90% w/w, most preferably 25% w/w to 75% w/w of the compound, with the remainder being the excipient or excipients.
Preferred compositions will include preferred compounds identified.
Some specific examples of suitable pharmaceutical compositions are described in Examples 7-9 below.
Typically, a pharmaceutical composition of the present invention would be packaged in a container with a label indicating use of the pharmaceutical composition in the treatment of hyperglycemia, Type I diabetes, and Type II diabetes, or a combination of any of these disease conditions.
(c) Preferred Methods of Use of the Compounds of the Present Invention.
Another aspect of the invention is directed towards methods of treatment administering the compounds of formula I or pharmaceutically acceptable salts thereof to a mammalian host. Preferred methods incorporate the administration of the preferred compounds identified.
Compounds of the present invention have been found to stimulate autophosphorylation of the insulin receptor (Example 5 below). In addition, these compounds have been shown to enhance insulin""s ability to effect the transport of glucose into cultured fibroblast cells (Example 6 below).
The ability of the compounds of this invention to stimulate autophosphorylation of the insulin receptor and to stimulate the uptake of glucose into cells, which is demonstrated in the specific examples, Examples 5 and 6 below, indicates their usefulness in the treatment and management of subjects with diabetes. Without intending to be bound by any theory, it is believed that the compounds of the invention act directly on the kinase function of the insulin receptor and do not necessarily compete with insulin for binding at the insulin-binding site, nor do they effect activation of the receptor by a mechanism similar to that exhibited by insulin. Thus, they are able directly to activate the kinase to autophosphorylate, to potentiate the effect of insulin, to activate the kinase function of the receptor in phosphorylating exogenous substrates and to effect the increased uptake of glucose by adipocytes and insulin receptor-bearing cells in general and to lower blood glucose in diabetic subjects. Accordingly, by virtue of the activities of the compounds of the invention, they may be used to stimulate the kinase activity of an insulin receptor, to enhance the activation of the insulin receptor by insulin, to enhance the stimulation by insulin of cellular glucose uptake, and to stimulate the uptake of glucose in diabetic subjects. Thus, the compounds of this invention are useful in the treatment of hyperglycemia and diabetes in mammals.
One aspect of the invention is directed to a method of stimulating the kinase activity of the insulin receptor. This method comprises contacting the insulin receptor, or the kinase portion thereof, with a compound of the invention in an amount sufficient to stimulate the kinase activity of the insulin receptor. By stimulating the kinase activity of the insulin receptor, both autophosphorylation and phosphorylation of exogenous substrates is enhanced. The stimulation of the kinase activity of the insulin receptor may occur either in vivo or in vitro. The method of stimulating the kinase activity of the insulin receptor may optionally further comprise contacting the insulin receptor with insulin.
In another embodiment of the invention, the insulin receptor is activated by contacting the insulin receptor, or the kinase portion thereof, with a compound of the invention in an amount sufficient to activate the insulin receptor. The targeted insulin receptor may optionally be on the surface of a cell in a mammal. In such a case, the contacting is effected by administering the compound, or a pharmaceutical composition thereof, to the mammal. Optionally, the method may further comprise contacting the insulin receptor with insulin.
In an alternative embodiment, the compounds of the invention are used to stimulate the uptake of glucose into cells displaying the insulin receptor. This method comprises contacting the cells in vitro or in vivo with a compound of the invention, optionally in the presence of insulin, and in an amount sufficient to stimulate the uptake of glucose into the cells. The targeted cells may optionally be in a mammal and the step of contacting the receptor with the compound may then be effected by administering the compound, or pharmaceutical composition thereof, to the mammal. In one embodiment of the method of stimulating the uptake of glucose into cells displaying the insulin receptor, the cells are also contacted with exogenous insulin.
A method of treating hyperglycemia or another disease involving an imbalance of glucose levels in a mammal, preferably a human, is also contemplated by the present invention. The method comprises administering a therapeutically effective amount of a compound of this invention, or a pharmaceutical composition thereof, to a mammnal. Optionally, the method may further comprise treating the mammal with one or more additional forms of therapy or treatment for hyperglycemia. For instance, one method may comprise administering exogenous insulin to the mammal in addition to the compound of the invention. Alternatively, the compounds of the invention may be administered to the mammal in combination with a non-insulin drug or other alternative treatment for hyperglycemia. The total amount of the combination of drugs administered to the mammal must be a therapeutically effective amount, although the amounts of each of the individual drugs may by themselves be sub-optimal for therapeutic purposes, and in particular the amount of insulin or the non-insulin drug or other alternative treatment for hyperglycemia or the other disease may be subtherapeutic if administered alone.
In one embodiment of the invention, the compounds are used to treat type I diabetes in a mammal. This method comprises administering a therapeutically effective amount of a compound of this invention, or a pharmaceutical composition thereof, to the mammal. In a preferred embodiment, the mammal is a human. The method of treating type I diabetes may optionally further comprise treating the mammal with one or more additional therapies or treatments for type I diabetes. For instance, in one embodiment of the method of treating type I diabetes, a compound of the invention and insulin may both be administered to the mammal. Alternatively, the additional form of treatment for type I diabetes which is combined with administration of the compound of the invention may be an antidiabetic agent other than insulin or another alternative form of treatment for type I diabetes. Again, the total amount of the combination of antidiabetic agents administered to the mammal must be a therapeutically effective amount, although the amounts of each of the individual drugs may be sub-optimal for therapeutic purposes if those drugs were to be delivered alone to the mammal with type I diabetes, and in particular the amount of insulin or the non-insulin drug or other antidiabetic agent or alternative treatment for type I diabetes may be subtherapeutic if administered alone.
In another embodiment of the invention, the compounds are used to treat type II diabetes in a mammal. This method comprises administering a therapeutically effective amount of a compound of this invention, or a pharmaceutical composition thereof, to the mammal. Again, the preferred subject is a human.
Again, like the other treatment methods of the invention, this method may farther comprise treating the mammal with one or more additional forms of therapy or treatment for type II diabetes, such as administering insulin to the mammal. The insulin is delivered to the mammal in an amount which is therapeutically effective when used in conjunction with a compound of the invention. This therapeutically effective amount of insulin when used in combination with a compound of the invention may be less than the amount of insulin which would be therapeutically effective if delivered to the mammal alone. It is understood that the insulin which is administered in any of the treatments of the present invention may either be isolated from a natural source or be recombinant. In addition, an insulin analog may be substituted for insulin in any of the treatments of the present invention.
Use of the compounds of the invention for treating type II diabetes by combination may also comprise the administration of the compound of the invention to the mammal in combination with a non-insulin antidiabetic agent or other treatment for type II diabetes. For instance, the antidiabetic drug which is administered to the mammal in combination with a compound of the invention may optionally be a thiazolidinedione, such as troglitazone, or a sulfonylurea. The total amount of the combination of drugs (invention compound plus insulin and/or other antidiabetic drug) administered to the mammal for the treatment of type II diabetes must be a therapeutically effective amount, although the amounts of each of the individual drugs used in the combination therapy may be sub-optimal for therapeutic purposes if those drugs were to be delivered alone to the mammal with type II diabetes, and in particular the amount of the non-insulin antidiabetic agent or other treatment for type II diabetes may be subthetapeutic if administered alone.
This invention also includes a method of obtaining and/or developing a compound that has the function of stimulating the kinase activity of the insulin receptor, activating the insulin receptor, and/or stimulating the uptake of glucose, by using a compound of this invention as a model. It also includes a method for identifying a compound which mimics the function of a compound of this invention, by submitting a test compound to a screen for determining its stimulation of the kinase activity of the insulin receptor relative to a compound of the invention; and identifying the test compound as one which mimics the function of a compound of this invention if it exhibits stimulation of the kinase activity of the insulin receptor. Another aspect of the invention is directed to a method for validating, optimizing, or standardizing a bioassay, comprising using a compound of this invention as a standard. A radiolabelled compound of this invention is also contemplated.
The compounds of this invention are, thus, used to enhance glucose uptake in patients which require such treatment. The method of treatment comprises administration parenterally and orally of a therapeutically effective quantity of the chosen compound of the invention, preferably dispersed in a pharmaceutical carrier. Dosage units of the active ingredient are generally selected from the range of 0.01-1000 mg/kg, preferably 0.01-100 mg/kg and more preferably 0.1-50 mg/kg. but will be readily determined by one skilled in the art depending upon the route of administration, age, and condition of the patient. The compounds of the invention are most preferably administered in a dosage unit of 1-10 mg/kg. These dosage units may be administered one to ten times daily for acute or chronic disease. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
The invention compounds may be administered by any route suitable to the subject being treated and the nature of the subject""s condition. Routes of administration include, but are not limited to, administration by injection, including intravenous, intraperitoneal, intramuscular, and subcutaneous injection, by transmucosal or transdermal delivery, through topical applications, nasal spray, suppository and the like, or may be administered orally. Formulations may optionally be liposomal formulations, emulsions, formulations designed to administer the drug across mucosal membranes, or transdermal formulations. Suitable formulations for each of these methods of administration may be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams and Wilkins, Philadelphia, Pa.
Processes for the preparation of the compounds of formula I comprise another aspect of the invention. Preferred processes generate the preferred compounds identified. In one embodiment of the invention, a compound of Formula I or a pharmaceutically acceptable salt thereof, can be prepared by a process comprising:
(a) reaction of an iodo-amide compound of the formula 
where R1-R7 are as defined above,
with a styrene or substituted styrene of the formula 
where R8-R10 are as defined above; or
(b) acylation of an aminostilbene of the formula 
where R5-R13 are as defined above,
with a compound of the formula 
where hal is chlorine or bromine, and R1-R4 and R11-R13 are as defined above; or
(c) chemical elaboration of one or more substituents R1-R10 where said substituent is convertible into another substituent R1-R10; or
(d) introduction of a substituent R1-R10 into one, two or all three of the phenyl rings; or
(e) deprotection of a protected group; or
(f) salt formation or interconversion; or
(g) ester or amide hydrolysis; or
(h) liberation of a free acid or base of a compound of Formula I, where R1-R12 are as defined above; or
(i) stereoisomer separation or synthesis.
The reaction of the iodo-amide compound with the styrene or substituted styrene shown in (a), above, can be carried out between 40xc2x0 C. and 120xc2x0 C. in the presence of such solvents as DMF, toluene, methylene chloride, or the like.
Chemical elaboration of one or more substituents R1-R10 via the conversion of one such substituent into another substituent may be accomplished via hydrolysis, salt formation, acidification, alkylation, esterification, oxidation, or reduction.
In hydrolysis, an ester or amide compound is dissociated by reaction with water. Hydrolysis is catalyzed by acid or base, and hydrolysis of an amide generally requires more vigorous conditions (for example, a higher concentration of sulfuric acid at 1-100xc2x0 C. for 1-5 hours) than those required for the hydrolysis of esters. Hydrolysis reactions can also be carried out with aqueous hydrochloric acid at 100-150xc2x0 C. and may require as long as 18 hours.
In salt formation, a free acid is converted into a salt via addition of a basic reagent, such as aqueous sodium hydroxide or triethanolamine, that replaces all or part of the hydrogen ions of the acid with one or more cations of a base. The conversion of a compound into its corresponding acid addition salt is accomplished via treatment with a stoichiometric amount of an appropriate acid, such as hydrochloric acid. Typically, the free base is dissolved in a polar organic solvent, such as methanol or ethanol, and the acid is added in methanol or ethanol. The temperature is maintained at 0-50xc2x0 C. The corresponding salt precipitates spontaneously or can be brought out of solution with a less polar solvent. In acidification, a chemical compound is converted into an acid.
In alkylation, an alkyl group is added to or substituted in a compound. Alkylation is carried out in a suitable solvent, such as acetonitrile, DMF, or THF, at 0-160xc2x0 C., typically at approximately 25xc2x0 C. to reflux, over approximately 1-18 hours.
An esterification reaction results in the formation of at least one ester product. In brief, the compound is reacted with from 1-5, preferably 2, molar equivalents of an alkanol, a thiol or ammonia, a monoalkylamine, or dialkylamine, or a heterocyclic aminoalkanol, optionally in the presence of from 1-1.5, preferably 1.25, molar equivalents of a tertiary organic base such as 4-dimethylaminopyridine or, preferably, triethylamine, in an organic solvent such as dioxane, tetrahydrofuran, or, preferably, dichloromethane. The reaction takes place between xe2x88x9210xc2x0 C. and 50xc2x0 C., preferably at ambient temperature, for 1-24 hours, preferably 4 hours.